Adrenergic neurons play a major role in innervating heart, blood vessel and smooth muscle tissue. Compounds capable of interacting with adrenoreceptor sites within adrenergic nerves can initiate a variety of physiological responses including vasodilation, vasoconstriction and increased or decreased heart rate (chronotropic), contractility (inotropic) and metabolic activity. Various adrenergic compounds have been previously employed to affect these and other physiological responses. However, many adrenergic compounds do not possess significant selectivity to enable desirable interactions with adrenergic adrenoreceptor sites. That is, these adrenergic compounds do not demonstrate a high degree of specificity for differing adrenoreceptor types within adrenergic neurons. Accordingly, they cannot selectively induce a desired physiological response apart from other possible, perhaps less desirable, responses.
Benign prostatic hyperplasia (also known as benign prostatic hypertrophy or BPH) is a condition which develops in middle-aged and elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate. Symptoms of BPH include increased frequency of urination, nocturia, a weak urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
The large numbers of .alpha.-adrenergic adrenoreceptors in the smooth muscle of the prostatic capsule and bladder neck indicate both a static and a dynamic component to bladder outlet obstruction associated with BPH. The static component derives from the progressive hyperplasia of the prostate with aging and leads to urethral narrowing which causes symptoms of urinary obstruction. In addition to this essentially mechanical problem, the amount of smooth muscle contraction controlled by the sympatheic nervous system varies with stress, cold and sympathomimetic drugs. This dynamic component explains the often rapid fluctuations in symptoms observed in patients with prostatism.
Currently, The most effective treatment for BPH is the surgical removal of the obstructing tissue, a treatment directed to both the static and dynamic components of BPH. However, this surgery has a 1% mortality rate in addition to significant risks of other adverse events (2-4% incontinence, 5-10% infection and 5-10% impotence).
Researchers have come to recognize the potential role of selective .alpha..sub.1 adrenoreceptor blockade in diseases of the lower urinary tract. Studies by several groups have documented the relative roles of .alpha..sub.1 adrenoreceptors and .alpha..sub.2 adrenoreceptors in the stromal compartment of the prostate, thereby providing a putative molecular basis for using .alpha..sub.1 adrenoreceptor specific blockers (.alpha..sub.1 antagonists) in the non-surgical management of BPH. Chapple et al., Br. J. Urol., v. 63, pp. 487-496 (1989). Clinical efficacy of .alpha..sub.1 antagonists in BPH has been demonstrated with several non-selective .alpha..sub.1 blockers including terazosin (Hytrin.RTM.), prazosin and doxazosin. Treatment periods as short as two to four weeks with .alpha..sub.1 adrenoreceptor blockers have shown objective improvements in the mean and maximum urinary flow rates (14-96%) with subjective improvements in patients' symptom scores. Janknegt et al., Eur. Urol., v. 24, pp. 319-326 (1993). Longer term studies with terazosin, indoramin, prazosin and doxazosin have similarly demonstrated significant improvements in urinary flow rates and subjective symptom scores. Lepor et al., J. Urol., v. 145, p. 263A (1991); Chow et al., Br. J. Urol., v. 65, pp. 36-38 (1990); Chapple et al., Urol. Int., v. 45, pp. 47-55 (1990). However, these agents possess similar dose-limiting side-effects such as hypotension, dizziness and muscle fatigue.
In recent years, it has become clear that BPH and bladder outlet obstruction (BOO) are clinically differentiable and that the severity of clinical BPH is related to many factors in addition to BOO. For example, BOO may be related to other urological symptoms such as detrusor instability. In addition, researchers postulate that .alpha..sub.1 adrenoreceptors outside of the prostate are also important in the etiology of lower urinary tract symptoms. They conclude that antagonizing these receptors in spinal cord, ganglia, nerve terminals, bladder and bladder neck or the external urethral sphincter can be important in the pharmacotherapy of urological conditions such as BOO and neurogenic bladder. Andersson, Scand. J. Urol. and Nephrol., v. 30, pp. 105-11 (1996).
Scientists have recognized that women possess paraurethral glands are anatomically, histologically and biochemically similar to the male prostate. This suggests a potential role for .alpha..sub.1 antagonist pharmacotherapy for ameliorating some symptoms of female urethral syndromes. In addition, researchers have also observed that .alpha.-adrenoreceptors are functionally important to smooth muscle contraction in the uterus and that the modulation of sympathetic responses to catecholamines is enhanced by elevated levels of estrogens. This is consistent with the increased .alpha.-adrenoreceptor response and receptor density following estrogen administration to animals. Thus hormonal regulation of .alpha..sub.1 adrenoreceptor sensitivity could play a role in enhanced uterine contractions in dysmenorrhea, a condition for which selective .alpha..sub.1 antagonists could have therapeutic potential.
It is apparent that a need exists for a "uroselective" .alpha..sub.1 antagonist with reduced side effects.